Tyrosine kinase inhibitors
View Patent ↗The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals.
1. A compound of Formula I
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
X is: C—H;
one n is 1 and one n is 2;
t is: 1 through 6;
R 1 is:
1) H,
2) halo,
3) C 1-6 alkyl, or
4) OC 1-6 alkyl;
R 2 is:
1) aryl, optionally substituted with one to three substituents selected from:
a) halo,
b) OC 1-3 perfluoroalkyl,
c) OC 1-6 alkyl,
d) CN,
e) OH,
f) SO 2 R d ,
g) C 1-6 alkyl,
h) i) (C═O)R d , and
i) CO 2 R d ,
2) CN,
3) (C═O)NR a R b ,
5) C 3-6 cycloalkyl, or
6) —C≡C—R c ;
R 3 is:
1) H,
2) C 1-8 alkyl,
3) SO 2 R d ,
4) (C═O)R d , or
5) CO 2 R d ;
R 3a is:
1) H,
2) SO 2 R d ,
3) heterocyclyl,
4) (C═O)R d ,
5) CO 2 R d , or
6) C 1-8 alkyl, said alkyl is optionally substituted with one to three substituents selected from oxo, heterocyclyl, halo, NR 5 R 6 , CO 2 H, CO 2 R d , CONR 5 R 6 , OH and OC 1-6 alkyl;
R 4 is:
1) H,
2) C 0-6 alkylene-NR 5 R 6 ,
3) CO 2 H,
4) CO 2 R d ,
5) halo,
6) OH,
7) C 1-8 alkoxy, or
8) C 1-8 alkyl, said alkyl is optionally substituted with one to three substituents selected from oxo, heterocyclyl, halo, NR 5 R 6 , CO 2 H, CO 2 R d , CONR 5 R 6 , OH and OC 1-6 alkyl;
R 5 and R 6 are independently:
1) H,
2) C 1-8 alkyl,
3) SO 2 R d ,
4) CO 2 R d ,
5) (C═O)R d ,
6) C 1-8 alkylene-NR a R b ,
7) C 1-8 alkylene-(CO)NR a R b ,
8) C 1-8 alkylene-heterocyclyl, or
9) aryl,
said aryl and heterocyclyl optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-3 perfluoroalkyl, C 1-6 alkoxy, OCF 3 , SO 2 R d , NR a R b and halo; or
R 5 and R 6 are taken with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring, said heterocycle optionally substituted with one or more substituents selected from halo, C 1-6 alkyl, OC 1-6 alkyl, OCF 3 , CO 2 R d , (C═O)R d , aryl, heterocyclyl, SO 2 R d and OH;
R a and R b are independently:
1) H,
2) C 1-6 alkyl,
3) C 3-6 cycloalkyl,
4) phenyl,
5) CO 2 R d ,
6) (C═O)R d , or
7) SO 2 R d ;
R c is H, phenyl, or C 1-6 alkyl; and
R d is phenyl or C 1-6 alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is:
a) phenyl, optionally substituted with one or two substituents selected from:
1) halo,
2) OC 1-3 perfluoroalkyl,
3) OC 1-6 alkyl,
4) CN, and
5) C 1-6 alkyl,
b) CN, or
c) (C═O)NR a R b .
3. The compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 , R 3 , R 4 are H.
4. A compound selected from:
N-(5-phenylthiazol-2-yl)-N′-[4-(2-pyridyl)piperazin-1-yl]urea;
N-(5-phenylthiazol-2-yl)-N′-[4-(2-pyrimidinyl)piperazin-1-yl]urea;
N-(5-phenylthiazol-2-yl)-N′-(4-aminopiperidin-1-yl)urea;
N-(5-phenylthiazol-2-yl)-N′-[4-(2-pyrimidinoxy)piperidin-1-yl)]urea;
N-(5-phenylthiazol-2-yl)-N′-(4-carboxypiperidin-1-yl)urea;
N-(5-phenylthiazol-2-yl)-N′-(3-carboxyazetidin-1-yl)urea; and
N-(5-phenylthiazol-2-yl)-N′-[4-(pyrrolidinocarbonylmethyl) piperazine-1-yl]-urea; or a pharmaceutically aceptable salt or steroisomer thereof.
5. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.